The bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: Findings of the death review committee of the national registry for individuals with severe deficiency of alpha-1 antitrypsin

doi:10.1016/j.humpath.2004.08.013

Human Pathology

Volume 35, Issue 12, December 2004, Pages 1452-1461

https://doi.org/10.1016/j.humpath.2004.08.013 Get rights and content

Abstract

To assess the pathological changes in the lungs and liver of 42 individuals who died while enrolled in the Registry of Individuals with Severe Deficiency of Alpha-1 Antitrypsin (AAT), all available histopathologic surgical or postmortem-derived specimens were reviewed by the pathologist member of the Death Review Committee. The underlying cause of death was emphysema in 34 patients and cirrhosis in 2 patients. Slides of lung were graded for emphysema, and liver specimens were graded for fibrosis, using respective pictorial scoring systems. Correlations between the degree of pathological abnormality and clinical features were evaluated. All lungs exhibited severe panacinar emphysema (mean emphysema score, 7.9 ± 1.06 [standard deviation], where 10 represents the greatest severity) with a lower lobe predominance. Centriacinar emphysema was minimal. No correlation was found between the pathological severity of emphysema and pulmonary function measurements, and no significant correlation was found between the degree of emphysema and the degree of hepatic fibrosis. Mildly increased bronchial gland-to-wall ratio accompanied mild inflammation and goblet cell hyperplasia. There were minimal changes in small airways. Dilatation of membranous bronchioles was a frequent finding; however, bronchiectasis of larger airways was a minor feature in only 6 patients (15%). Airway morphological features did not correlate with the clinical presence of chronic bronchitis or asthma. Although the lack of correlation between liver and lung pathological changes may reflect different pathogenetic mechanisms of liver disease and lung disease, the lack of correlation between emphysema grade and lung function likely reflects the skewed sample in a series of patients with advanced lung disease.

Section snippets

Patients and methods

Of the 1129 Registry enrollees, 204 (18.1%) had died by the end of the Registry follow-up. Medical records were available for 120 decedents (59%). Autopsies were performed in 38 (32%) decedents, and slides were reviewed in 34 cases (89%). Twenty-five (21%) of the 120 subjects underwent lung transplantation, and slides of the native lung explants were reviewed in 23 cases (92%). A nonblinded reviewer (J.F.T.) reviewed histological slides of native lung tissue from 42 participants, who compose

Patient population and causes of death

Demographic and clinical features of the 42 patients are presented in Table 1. All patients had severe emphysema due to AAT deficiency as determined by clinical parameters, chest x-rays, and pulmonary function tests. The underlying and immediate causes of death as determined by the DRC are listed in Table 2.

Emphysema

All lungs were affected by severe panacinar emphysema, with a mean emphysema score of 7.9 ± 1.06 FIGURE 1, FIGURE 2. Focal centriacinar emphysema was observed infrequently. The

Discussion

The present study of native lungs from individuals with severe AAT deficiency confirms previous observations based on small series or individual patients.3, 4, 5, 6, 7, 8, 9, 10, 11, 12 The main findings from the current study are as follows:

1.
Panacinar emphysema was a universal feature of the lungs examined in this series.
2.
The emphysema (Nagai) score did not correlate with measurements of the diffusing capacity, percent predicted FVC, or percent predicted FEV-1.
3.
Bronchiectasis was an uncommon

Acknowledgements

The authors thank Dr. Joanne Wright for providing the poster used for grading small airways, and Ms. Susan Sherer for support in data collection and analysis.

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Small airways disease in patients with alpha-1 antitrypsin deficiency
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Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder, characterized by panacinar emphysema mainly in the lower lobes, and predisposes to chronic obstructive pulmonary disease (COPD) at a younger age, especially in patients with concomitant cigarette smoking. Alpha-1 antitrypsin (a1-AT) is a serine protease inhibitor that mainly blocks neutrophil elastase and maintains protease/antiprotease balance in the lung and AATD is caused by mutations in the SERPINA1 gene that encodes a1-AT protein. PiZZ is the most common genotype associated with severe AATD, leading to reduced circulating levels of a1-AT. Besides its antiprotease function, a1-AT has anti-inflammatory and antioxidative effects and AATD results in defective innate immunity.
Protease/antiprotease imbalance affects not only the lung parenchyma but also the small airways and recent studies have shown that AATD is associated with small airway dysfunction. Alterations in small airways structure with peripheral ventilation inhomogeneities may precede emphysema formation, providing a unique opportunity to detect early disease. The aim of the present review is to summarize the current evidence for the contribution of small airways disease in AATD-associated lung disease.
Augmentation therapy with human alpha-1-proteinase inhibitor reduces exacerbations in patient with bronchiectasis and alpha-1-antitrypsin deficiency
2022, Respiratory Medicine Case Reports
Alpha-1-antitrypsin deficiency (AATD) is a rare cause of noncystic fibrosis (CF) bronchiectasis. The benefits of augmentation therapy in patients with chronic obstructive pulmonary disease (COPD) and pulmonary emphysema are well established. The role of augmentation therapy in AATD bronchiectasis in patients without pulmonary emphysema is not clear.
We present the case of a 53-year-old woman (never smoker) who presented with increased susceptibility to infection, productive cough, and intermittent hemoptysis. Pulmonary function testing revealed restrictive impairment [VC 2,7 l (83% of pred.), FEV1 2,3 l (86% of pred.)]. A CT scan of the chest showed marked basal bronchiectasis with mucoid impaction, surrounding consolidation, and no emphysema. Despite frequent use of inhalation therapy, a satisfactory control of symptoms and exacerbations was not achieved.
In the course of extended diagnostics regarding the genesis of bronchiectasis, a reduced alpha-1-antitrypsin (AAT) serum level was detected, and a genetic test revealed a homozygous Pi*ZZ genotype. We started augmentation therapy with AAT (Respreeza®, CLS Behring) at the dose of 60 mg/kg per week; the therapy was well tolerated by the patient, and she reported clinical improvement with a reduction in exacerbation frequency.
AAT is a serine protease inhibitor and plays a major role in regulating inflammatory activities, in particular by inhibiting neutrophil elastase (NE). The present case illustrates the positive effect of augmentation therapy, including patients without airway obstruction. Among other causes, AATD should be considered as a possible cause of bronchiectasis, and the effects of augmentation therapy for this indication need to be prospectively studied.
Delivery of genome-editing biomacromolecules for treatment of lung genetic disorders
2021, Advanced Drug Delivery Reviews
Citation Excerpt :
The classical clinical presentation of AATD-associated lung disease is severe whole-lung panacinar and lower lobe-predominant emphysema [59]. Although AATD shares many similar clinical characteristics with emphysema, the pathology features of AATD fundamentally differ from common emphysema [60]. Patients with AATD can also progress into COPD, which is often triggered by interactions between environmental and genetic factors [61].
Genome-editing systems based on clustered, regularly interspaced, short palindromic repeat (CRISPR)/associated protein (CRISPR/Cas), are emerging as a revolutionary technology for the treatment of various genetic diseases. To date, the delivery of genome-editing biomacromolecules by viral or non-viral vectors have been proposed as new therapeutic options for lung genetic disorders, such as cystic fibrosis (CF) and α-1 antitrypsin deficiency (AATD), and it has been accepted that these delivery vectors can introduce CRISPR/Cas9 machineries into target cells or tissues in vitro, ex vivo and in vivo. However, the efficient local or systemic delivery of CRISPR/Cas9 elements to the lung, enabled by either viral or by non-viral carriers, still remains elusive. Herein, we first introduce lung genetic disorders and their current treatment options, and then summarize CRISPR/Cas9-based strategies for the therapeutic genome editing of these disorders. We further summarize the pros and cons of different routes of administration for lung genetic disorders. In particular, the potentials of aerosol delivery for therapeutic CRISPR/Cas9 biomacromolecules for lung genome editing are discussed and highlighted. Finally, current challenges and future outlooks in this emerging area are briefly discussed.
Diagnostic evaluation of bronchiectasis
2019, Respiratory Medicine: X
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In a study of over 200 bronchiectasis patients, the frequency of abnormal AAT genotypes was not significantly different than those without bronchiectasis [38]. In contrast, others have found an association between frank AAT deficiency and bronchiectasis [39–42]. Guest and Hansell [39] examined the CT scans in 17 patients with proven AAT deficiency and found that 7 of the patients had bronchial wall thickening and/or dilatation and one had gross cystic bronchiectasis.
Bronchiectasis should be considered in anyone with chronic cough and sputum production. High resolution CT is the diagnostic test of choice for diagnosis of bronchiectasis, showing dilated non-tapering bronchi especially into the peripheral lung, increased ratio of the bronchial:arterial diameters, and occasionally mucous plugs within the dilated bronchi. Once a diagnosis of bronchiectasis is made, clinicians must determine whether workup for a predisposing cause is necessary and what diagnostic tests to obtain. Herein, we provide a brief synopsis of the known causes of bronchiectasis with a primary focus on the diagnostic tests that can help uncover an underlying vulnerability to bronchiectasis.
Emphysema and Diseases of Large Airways
2018, Pulmonary Pathology: A Volume in the Series: Foundations in Diagnostic Pathology
Alpha-1-antitrypsin deficiency: Genetic variations, clinical manifestations and therapeutic interventions
2017, Mutation Research - Reviews in Mutation Research
Citation Excerpt :
Carriers with the MZ alleles, however, may have an increased risk for lung disease, particularly if they smoke. AATD can lead to lung disease (emphysema and bronchiectasis) [67] liver disease (chronic hepatitis, cirrhosis and hepatoma) [27] and skin diseases (Panniculitis) [68]. However the major clinical manifestations are in the form of lung and liver disease, there are some other diseases associated with AATD but are very rare (Vasculitis, glomerulonephritis and celiac disease) [69], intracranial and intra-abdominal aneurysms [70], fibromuscular dysplasia [71] and pancreatitis [72].
Alpha-1-antitrypsin (AAT) is an acute phase secretory glycoprotein that inhibits neutrophil proteases like elastase and is considered as the archetype of a family of structurally related serine-protease inhibitors termed serpins. Serum AAT predominantly originates from liver and increases three to five fold during host response to tissue injury and inflammation. The AAT deficiency is unique among the protein-misfolding diseases in that it causes target organ injury by both loss-of-function and gain-of-toxic function mechanisms. Lack of its antiprotease activity is associated with premature development of pulmonary emphysema and loss-of-function due to accumulation of resultant aggregates in chronic obstructive pulmonary disease (COPD). This’ in turn’ markedly reduces the amount of AAT that is available to protect lungs against proteolytic attack by the enzyme neutrophil elastase. The coalescence of AAT deficiency, its reduced efficacy, and cigarette smoking or poor ventilation conditions have devastating effect on lung function. On the other hand, the accumulation of retained mutant proteins in the endoplasmic reticulum of hepatocytes in a polymerized form rather than secreted into the blood in its monomeric form is associated with chronic liver disease and predisposition to hepatocellular carcinoma (HCC) by gain- of- toxic function. Liver injury resulting from this gain-of-toxic function mechanism in which mutant AAT retained in the ER initiates a series of pathologic events, eventually culminating at liver cirrhosis and HCC. Here in this review, we underline the structural, genetic, polymorphic, biochemical and pathological advances made in the field of AAT deficiency and further comprehensively emphasize on the therapeutic interventions available for the patient.

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^☆: Supported by a grant (NO1-HR-86036) from the National Heart, Lung, and Blood Institute, National Institutes of Health.

^∗: See the Appendix for study group membership.

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Original contributionsThe bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: Findings of the death review committee of the national registry for individuals with severe deficiency of alpha-1 antitrypsin☆

Abstract

Section snippets

Patients and methods

Patient population and causes of death

Emphysema

Discussion

Acknowledgements

Am J Med

Chest

Am J Med

Am J Med

Chest

Clinical Radiology

Chest

Chest

Chest

Alpha-1-antitrypsin deficiencyan introduction

Clinical features of the destructive lung disease associated with alpha-1-antitrypsin deficiency in adults with pulmonary symptoms

Am Rev Respir Dis

The lungs in homozygous alpha-1-antitrypsin deficiency

Am J Clin Pathol

Studies in alpha 1-antitrypsin deficiency

Acta Med Scand

Pathological findings in alpha-1 antitrypsin deficiency

Original contributions
The bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: Findings of the death review committee of the national registry for individuals with severe deficiency of alpha-1 antitrypsin☆